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A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis [Single cell RNAseq]

ABSTRACT: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of myocarditis, characterized by sustained NF-kB activity, associated with decreased gene expression of NF-kB inhibitors and TNF-a signaling . We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1a and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167029 | GEO | 2021/07/13

REPOSITORIES: GEO

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A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis [Bulk RNAseq]

Project description:SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of myocarditis, characterized by sustained NF-kB activity, associated with decreased gene expression of NF-kB inhibitors and TNF-a signaling . We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1a and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology.

2021-07-13 | GSE167028 | GEO

Multisystem inflammatory syndrome in children (MIS-C) serum proteomics

Project description:While fewer cases of severe Coronavirus Disease 2019 (COVID-19) are reported globally in children, a small proportion of SARS-CoV-2 infected children develop a novel pediatric febrile entity called multisystem inflammatory syndrome in children (MIS-C) that develops 2 to 5 weeks after initial SARS-CoV-2 exposure. MIS-C primarily effects male children and children of Hispanic or black descent. MIS-C manifests as a severe and uncontrolled inflammatory response with multiorgan involvement. A hyperinflammatory state is evidenced by clinical makers of inflammation including high levels of C-reactive protein (CRP), ferritin, and D-dimers, and an increased expression of pro-inflammatory cytokines. Children often present with persistent fever, severe gastrointestinal symptoms, cardiovascular manifestations, respiratory symptoms and neurological symptoms6-11,13. Cardiovascular manifestations include hypotension, shock, cardiac dysfunction, myocarditis and pericardial effusion. In the united states, admission to the intensive care unit occurs in approximately 58% of cases. To understand disease pathogenesis of MIS-C and proteins associated with the severe form of disease we performed proteomics analysis of serum or plasma samples. We collected serum from healthy children (SARS-CoV-2 negative, n=20), mild MIS-C (non-ICU, n=5) and severe MIS-C (ICU, n = 20) patients. MIS-C definition and diagnosis was performed according to CDC guidelines. Healthy adult serum (n = 4) was also used for reference ranges quality control and we obtained plasma samples from Kawasaki Disease (KD; n=7) patients that were recruited before the Coronavirus Disease 2019 (COVID-19) pandemic.

2021-09-29 | PXD025462 | Pride

Neutrophil profiles of pediatric COVID-19 and multisystem inflammatory syndrome in children

Project description:Multisystem Inflammatory Syndrome in Children (MIS-C) is a delayed-onset, COVID-19-related hyperinflammatory illness characterized by SARS-CoV-2 antigenemia, cytokine storm, and immune dysregulation. In severe COVID-19, neutrophil activation is central to hyperinflammatory complications, yet the role of neutrophils in MIS-C is undefined. Here, we collect blood from 152 children: 31 cases of MIS-C, 43 cases of acute pediatric COVID-19, and 78 pediatric controls. We find that MIS-C neutrophils display a granulocytic myeloid-derived suppressor cell (G-MDSC) signature with highly altered metabolism, distinct from the neutrophil interferon-stimulated gene (ISG) response we observe in pediatric COVID-19. Moreover, we observe extensive spontaneous neutrophil extracellular trap (NET) formation in MIS-C, and we identify neutrophil activation and degranulation signatures. Mechanistically, we determine that SARS-CoV-2 immune complexes are sufficient to trigger NETosis. Our findings suggest that the hyperinflammatory presentation during MIS-C could be mechanistically linked to persistent SARS-CoV-2 antigenemia, driven by uncontrolled neutrophil activation and NET release in the vasculature.

2022-11-05 | GSE217370 | GEO

Diagnosis of multisystem inflammatory syndrome in children (MIS-C) by a whole-blood transcriptional signature

Project description:Multisystem inflammatory syndrome in children (MIS-C) occurs in some children approximately 2-6 weeks following infection with SARS-CoV-2. Clinical symptoms are highly overlapping with Kawasaki disease (KD) and bacterial (DB) and viral (DV) infections, making diagnosis particularly challenging. Host whole blood transcriptomics can reveal specific combinations of host genes whose expression patterns can distinguish between disease groups of interest. We performed whole blood RNA-Sequencing of individuals with MIS-C, KD, bacterial and viral infections to identify a number of host genes that, when combined, could be used to diagnose MIS-C. This data contains processed data only. Raw data will be available via a controlled access archive.

2023-06-27 | E-MTAB-12793 | biostudies-arrayexpress

Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis

Project description:Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines, yet the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated the systemic immunopathological landscape underlying such rare cases of myopericarditis occurring after SARS-CoV-2 LNP-mRNA vaccination using peripheral blood single-cell transcriptome and repertoire sequencing, among other multimodal approaches.

2023-05-04 | GSE230227 | GEO

Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium

Project description:The SARS-CoV-2 novel coronavirus global pandemic (COVID-19) has led to millions of cases and hundreds of thousands of deaths globally. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally-resolved immunofluorescence in mouse and human lung tissue, we found expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.

2020-11-13 | GSE160876 | GEO

Immunological role of platelets in Theiler’s virus-induced inflammatory demyelinating disease and myocarditis

Project description:Platelets have been immunologically associated with viral and immune-mediated diseases such as Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) and Experimental autoim-mune encephalomyelitis (EAE). However, the role of platelets in Theiler’s murine encephalo-myelitis virus (TMEV)-induced myocarditis and inflammatory demyelination disease (IDD) is still unknown. We determine whether platelets were associated with TMEV infection and whether glycoprotein Ib alpha chain (GPIbα/CD42b) antibody injection could affect the pathogenicity of TMEV-induced myocarditis and TMEV-IDD. We conducted a mechanistic experiment by injecting TMEV-infected mice with the anti-GPIbα antibodies 0 and 5 days p.i. (“Early” group) or 18 and 22 days p.i. (“Late” group). Using in silico and in vivo approaches, we found platelets and platelet-related genes were associated with TMEV infection. Platelet depletion in Early and Late mice reduced fibrotic area in the heart, inflammatory demyelinating lesions with lower viral persistence in the CNS and altered antiviral antibody responses. Thus, platelets contribute to the pathogenesis of TMEV infection by promoting fibrosis and CNS inflammation. Platelet-depletion treatment might open new therapeutic approaches for TMEV-induced myocarditis and TMEV-IDD.

2024-03-20 | GSE253385 | GEO

Blood RNA-seq data from individuals during the UK Covid-19 lockdown, spanning sequential weeks from first PCR-confirmed SARS-CoV-2 infection, used to evaluate blood transcriptomic signatures of viral infection and identify host-response biomarkers of early SARS-CoV-2 infection

Project description:Healthcare workers were recruited at St Bartholomew’s Hospital, London, UK in the week of lockdown in the United Kingdom (between 23rd and 31st March 2020). Participants underwent weekly evaluation using a questionnaire and biological sample collection (including serological assays) for up to 16 weeks when attending for work and self-declared as fit to attend work at each visit, with further follow up samples collected at 24 weeks. Blood RNA sequencing data was to be used to identify host-response biomarkers of early SARS-CoV-2 infection, to evaluate existing blood transcriptomic signatures of viral infection, and to describe the underlying biology during SARS-CoV-2 infection. This submission includes a total of 172 blood RNA samples from 99 participants. Of these, 114 samples (including 16 convalescent samples collected 6 months after infection) were obtained from 41 SARS-CoV-2 cases, with the remaining 58 from uninfected controls. Participants with available blood RNA samples who had PCR-confirmed SARS-CoV-2 infection during follow-up were included as ‘cases’. Those without evidence of SARS-CoV-2 infection on nasopharyngeal swabs and who remained seronegative by both Euroimmun anti S1 spike protein and Roche anti nucleocapsid protein throughout follow-up were included as uninfected controls. ‘Cases’ include all available RNA samples, including convalescent samples at week 24 of follow-up for a subset of participants. For uninfected controls, we included baseline samples only. Sample class denotes weekly interval to positive SARS-CoV-2 PCR; non-infected controls (NIC); convalescent samples (Conv)_.

2021-07-07 | E-MTAB-10022 | biostudies-arrayexpress

Differential expression profiles of plasma tsRNAs in children with fulminant myocarditis

Project description:We report the application of high-throughput RNA sequencing technology to examine expression profiling of plasma transfer RNA (tRNA)-derived small RNAs (tsRNAs) in children with fulminant myocarditis during acute phase (FM-A group), children with fulminant myocarditis during convalescent phase (FM-C group), and healthy volunteers (Con group). A total of 750 precisely matched tsRNAs were identified in the plasma from the three groups. We find that a total of 13 tsRNAs were differentially expressed in FM-A and CON samples, of which 11 tsRNAs were upregulated and 2 were downregulated, and 694 tsRNAs were excluded ; a total of 8 tsRNAs were differentially expressed in paired FM-C and CON samples, of which 2 tsRNAs were upregulated and 6 were downregulated and 703 tsRNAs were excluded . This study provides new ideas for future research on elucidating the mechanisms of myocarditis through regulating tsRNAs levels.

2020-12-29 | GSE163944 | GEO

Comparative Pathogenesis of Three Human and Zoonotic SARS-CoV Strains in Cynomolgus Macaques

Project description:The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. Host responses to the three SARS-CoV strains were similar and only apparent early during infection with the majority of genes associated with interferon signalling pathways.This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use 4 strains, time course, lungs

2011-08-31 | E-GEOD-23955 | biostudies-arrayexpress

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